J\CC \.I,. Ninumh
IX. \in 5 I WY, Il!r
,223
-
High Dose Titration of Cal& Pulmonary Hypertension: Gu STUART ClIh qw.
RICH. ,,,i,wir
MD.
FACC.
ELI%.ADEl-H
ary
K-\Li-\I.\UN.
RN
rcnn. pulmonary function te+ting. echocardiography and the alwnce of left :o rtghr shunting and clcvalcd Icft heart prcswre\ on cathctcriratmn. nccording to thl: protocol of the National Inxtitntc~ of Heahh Primary Pulmonary Hyperlen\ton Rcgbtry 16). naseline ficmnd~namic measurements. Diagnostic right heart catheterization WI pcrformcd on all palicnlb after an overnight fa\l. All mcdtcation\. with the exceplion of digown tmd diuretic\. wcrc dixontinued for at least 2 weeks hcforc lhc wdy. Palwnt~ not receiving digoain bcpan treatmcnt with rheadrug hefore hospital ndmibaion. Systemic and prtlmonary ttrtcry preawes and cardiac output by thermodi. lut~on technique were mcasurcd. with vt~lucs for pulmonary viwzttlar rc,ittancc and systemic vascular re*istance calcu. lt~red according to standard formulab. Placement of the EBI~EICI~ w+\ performed in the cardiac catheterization lab. oratory. The paticntr were transferred to the coronary citrc unit with a thermodilutiun flow-directed catheter in the pulmonary artery and a bmttll ttrterial cannula in the femural artcry for drug cr’alua~ton. Patients were allowed 3 IO 4 h In bccomc occlimtncd to the coronary care unit wrounding\. A minimum ofihrcc rccordine% 3U min aparl. were ohiaincd toestahlich hwline hcmodynamic vaiue~ before initiation of the drug study. Acute calcium channel hlockcr challenge. All ptlienls rcccived an inilinl challenge of a ~wt~en~~onal oral dose of nifcdiptne I20 mg. 42 patients1 or diltiazem 0% mg, 5 parienlst. with hcmodynamic mearuremcnt~ made alter I h. Consecutive oral doses of either nifcdipinc or dihiazem were then administered hourly to the paricnts: until It a positive rcvonsr occurred ldefmed as tt dccreasc in both mean pulmonary artery prcsrnrc and pulmonary vascular reststance Gth no further decrease aRer one additional doset. ?I the patienl experienced an adverse effect of the drug requiring IIIdiacwtinuution. or 3) IO consecutive hourly dew were given. Fur purposes of thb study. 2tJ mg of nifedipmc and 60 ntg of diltiazem wcrc considered to be cquwelent oral doses. Nifedipine was rclccted ttnlebs the paticnl had a heart rate at rest >I00 bcatalmin. In patienls who had a favorahlo response. halfof the cumulative dose of drug deemed e&&e ww rhen readministcrcd every 6 IO 8 h (dcpcndina on Ihe duration of actionl over a 24-h period. Final hemodynamic rneesurcmcnts were made I h afterthe last dose. Characterization of the hemadynamic response. For pw pores of analysis of the effect of the drug challcngea. four types of responses were characterized. A “pressure rc. spender” was defined a$ a patient who had :I 20% reduction in rncsn pulmonary artery pressure. with a Gnthtr or grcaler reduction in calculated pulmonary vascular rcci~tance. A ‘*rcsi%ancc responder” was a patient who had il reduclion of %20% in pulmonary vascular resistance hut of ~20% in mean pulmonary artery pressure. Patients who did “01 have a reduction of 2OR in either pulmonary artcry presserc or pulmonary vascttlar resistance were considered nonresponderb. Patients who were unable to tolerate more than a
Gtgle dare uf the owl calcium blocker VW considered 4s a ,eparate proup. Statistical analysis. Mean vatucs ? SD were computed for all variahlec measured. Comoarirons between control and treated statea were made bv wired Student’s r test. Difference\ hetwecn the cfTect nf’conventional and high doses of the drug were evaluated with McNcmar’s WSI. Compariwm between the rcbponses of edch ofthe different groups were mude with one-way analysis of variance.
Results “Prew~re responders” (Pig. It. The baseline demoFraphic and hemodynamic chsracteristics and response IO calcium channel blockers of the patients arc noted in Table I, Fifteen patients were characterized as “pressure responder+..” As a proup. thcw patients had .I reducric,t in mean pulmonary awry prwure of 6.8 i 6% Ip = NS) and a I? * 25% :cducliun in pulmonary vascular resistnnce Ip C 0.05) after the first dox of a calcium channel blocker. After maximal dose challenges. the reduction in mean pulmonnry artery preswrc wtts 36.2 - 8% tp c 0.01) and in pulmonary vascular rebirldncc ws 5 0. 2 i 7% tp < 0.01). This response was associated .with a 22.7 2 1% increase in cardiac outpur Ip < 0.011 and a IO.8 z II% reduction in mean systemic presswe tp C U.ttl L No bignilicant change in heart rate. right atria1 pressure or wedge pressure wns ohserved. Resbtance responders (Fig. 21. Nineteen patients were chardcterizcd as “resistance wponders.” In this group. the reduction in mean pulmonary arlcry pressure after the initial dose of blocker was 5.7 % a% tp = NS) wherexthc reducrion in pulmonary vascular resi~ttancc wa, 21.8 5 IY% Ip < O.Illk Althuugh there was il significam reduction lranpe 5.9% lo 12%: p < tI.USI in mean syxtcmic arterial pressure with rhe maximal doire. tno further +tiiivant reduction in pulmonary artery prw,[lre 110.6 r II%) or pulmonttry vascular reriwnce t25.2 5 12%) occurred 81 the maximal
calcium
dose when during
values
were
in mew
compared
wilh
the first dose. This group alw
increase in cardiac wtp! systemic
Ihow
meawrcd
maniie*ted
a lY.i?
‘p < 0.01 I and an I I .W
reduction
pressure tp < 0.05) with
no significant
change in heart rate. nghl alrial prewre or pulmonary capillary wedge pressure. The number of do% qurcd 10 achieve maximal effecr% in the pressure and rewt.mcc responders
was 6 ? 2. I (range 3 to 111,
Nmresuonden.
Ten
palienls
were
conridered
nunrc-
who have more were hemodynamic changes arc le% likely w rc\pond 10 Ihe calcium channel blockers. Howcvcr. hecaurc we were un;rhle ro clearly dcwihc a clinical profile of a patienl who will not respond to drug challenge. we rcm;dn ohligawd 10 te\t all patients with primary pulmonary h!prrren\ion ID elucidate whether the drugs might he of ootential hemodvnamic benefit. Mechanism oire5ponses. The mea logtcal explanation for the different recpowe, to the calcium channel blockers is th;u they reprerem dift’erenr lev& of reverity of pulmonary VBIEU~K disc&e IOI. Thw. preswe rewmders would cornwise rhrne oatienl~ whose pulmonary vascular bed has the &te~r po&ial fordilalion and who therefore probably have ICII advanced di%a% The preferential influence ofthe calcium hlocken on the mdmonarv vas~ularure in lhesc paen!\ wggcxt\ heightened vawular lone in the pulmonary bed (5.10.1 Paticnl\ chardclerixd as resisumce rerponderr probably have more advanced pulmonary vawdar discart. The calcium blockers permit these patientr to adjurt to an increased cardiac output without causing a change i? pulmonary ancry preswre. However. the level of vssodilatton I\ inwfficiem to cause a Ggnificanl decrease in pulmonary awry prewre. Thw patients had comparable reductmn~ in w\ternic vaxular resistance as well. suggesting that the calcium blockers were working nonprefer&ially. Palwnts clarified as nonresponders probably have even more advanced pulmonary &ular d&se whh B fixed pulmonary varcular rcGs!ance. These patients exhihircd a reduction only in systemic vascular resiswtce. Adverse effeels. Six percent of Ihe patients tested were unable lo tokrac more than a single dose of the calcium blocker. These palicnrb probably had advanced dlseasc avocialcd with %vere right ventricular dysfunction. The onset oi hypolemion in these patients was associated with an increase in right atria1 pressure and a reduction in cardiac output. Thu\ it probably represented a negative inotropic efiect on a dysfunctional right venrricle in Ihe setting of a pulmonary vasculilr hed that has fixed pulmonary vascular rc~rlance. These ohservalions underscore the need to pay strict allention lo all hemodynamic variables. not just systemic and mdmonary artery pres~urt. when lestine vasodilators in &en!\ &h pul&~ary hypertension. _ Indication for hemcdynmnic monlloring. Our experience alw dictate\ SKI! varodilalor drugs should be administered initially IO pcllicnt> with pulmonary hypertension only with direct hemcdynamic monhoring. Whhout it. the physician cannot know how 10 adjurt Ihe dose for the patient’s maximitl hcnelicial &cl or monhor while changcel suggesting adverse hemodynamic elTec& tha might prove camrlrophic. Although we had no mortality or scrwn~~ morbidily in amv of the oauems that WC tested. adverse etl’ectr of these drug; and dealhs have been previously reported 12-141 and should not be Ignored. II iq our practice to either inhiate or mainlain digorin therapy in all ~atienis undergoing drug teuinp with the premix thal digoxin might counleracr neg_ alive inolropic effects of the calcium blockers. This hypoth-
t
IL
we hmiiedLour te\ling’ to the r/n&-d& challenges commonlv used bvolhcr invcsliealor\ 13.3.7l. we would rrol have identified the porenrial of high dew 10 caux a Ikrrge redw lion in pulmonary artcry pressure. II is presumed lhat these high dose\ arc ncedcd hecause of the high level of v:~wcorv striction wilhin rhe puhnonary arteries. It i\ also pwrihl: that the higher doles elicit other propertie\ of Ihc calcium chnnncl blockers lhal arc nol mediillcd by lhur iiclions on vol!age-dependent calcium channrls. such as modulation of the nucleoride Iran\porler. which could aRccl adenorinc uptake by crythrocyter IR). A Z!O% reduction of pulmonary vwcul~r reiiamce without substantral changes in pulmonary anery preswre was the most common response (40%). Parienl\ whh Ihl, response had an mcrease in cardiac output and a dccrcarc in pulmonary wscuIa resirlance. but not 10 Ihe magnitude of the pressure recpon\e group and not to the point where the pulmonary artery pwwre was significantly reduced. In Ihi\ croup the hirher doses of the u!cium hlockcr reruhed in iirrle. further-reduclion in pulmonary wcular resist;mcc from lhat achieved with the milial dews. Conxquenlly. we recommend that such paUerxa. if wealed with a udcium blocker on B long.term hai%. he given the lowc~t effective dose that i\ identified. Among the potential advew ~Kects of the calcium blockers are negahvc inolropic properlie< that could imparr righl ventricular performance and potenliully affect lone-term morhidhv ad rnorlalitv 19). Predicting the lypp of response. One of our more surpns. ing finding5 WBF our inabihly to predict Ihe type of re\ponre to drug testing o)n the bui, of a paliem‘r rympmms or baseline hemodynarmc status. It remains our hia\ that pa. lienfs who have had symptoms for longer perrod, of lime and
t
IX. \in 5 I WY, Il!r
,223
-
High Dose Titration of Cal& Pulmonary Hypertension: Gu STUART ClIh qw.
RICH. ,,,i,wir
MD.
FACC.
ELI%.ADEl-H
ary
K-\Li-\I.\UN.
RN
rcnn. pulmonary function te+ting. echocardiography and the alwnce of left :o rtghr shunting and clcvalcd Icft heart prcswre\ on cathctcriratmn. nccording to thl: protocol of the National Inxtitntc~ of Heahh Primary Pulmonary Hyperlen\ton Rcgbtry 16). naseline ficmnd~namic measurements. Diagnostic right heart catheterization WI pcrformcd on all palicnlb after an overnight fa\l. All mcdtcation\. with the exceplion of digown tmd diuretic\. wcrc dixontinued for at least 2 weeks hcforc lhc wdy. Palwnt~ not receiving digoain bcpan treatmcnt with rheadrug hefore hospital ndmibaion. Systemic and prtlmonary ttrtcry preawes and cardiac output by thermodi. lut~on technique were mcasurcd. with vt~lucs for pulmonary viwzttlar rc,ittancc and systemic vascular re*istance calcu. lt~red according to standard formulab. Placement of the EBI~EICI~ w+\ performed in the cardiac catheterization lab. oratory. The paticntr were transferred to the coronary citrc unit with a thermodilutiun flow-directed catheter in the pulmonary artery and a bmttll ttrterial cannula in the femural artcry for drug cr’alua~ton. Patients were allowed 3 IO 4 h In bccomc occlimtncd to the coronary care unit wrounding\. A minimum ofihrcc rccordine% 3U min aparl. were ohiaincd toestahlich hwline hcmodynamic vaiue~ before initiation of the drug study. Acute calcium channel hlockcr challenge. All ptlienls rcccived an inilinl challenge of a ~wt~en~~onal oral dose of nifcdiptne I20 mg. 42 patients1 or diltiazem 0% mg, 5 parienlst. with hcmodynamic mearuremcnt~ made alter I h. Consecutive oral doses of either nifcdipinc or dihiazem were then administered hourly to the paricnts: until It a positive rcvonsr occurred ldefmed as tt dccreasc in both mean pulmonary artery prcsrnrc and pulmonary vascular reststance Gth no further decrease aRer one additional doset. ?I the patienl experienced an adverse effect of the drug requiring IIIdiacwtinuution. or 3) IO consecutive hourly dew were given. Fur purposes of thb study. 2tJ mg of nifedipmc and 60 ntg of diltiazem wcrc considered to be cquwelent oral doses. Nifedipine was rclccted ttnlebs the paticnl had a heart rate at rest >I00 bcatalmin. In patienls who had a favorahlo response. halfof the cumulative dose of drug deemed e&&e ww rhen readministcrcd every 6 IO 8 h (dcpcndina on Ihe duration of actionl over a 24-h period. Final hemodynamic rneesurcmcnts were made I h afterthe last dose. Characterization of the hemadynamic response. For pw pores of analysis of the effect of the drug challcngea. four types of responses were characterized. A “pressure rc. spender” was defined a$ a patient who had :I 20% reduction in rncsn pulmonary artery pressure. with a Gnthtr or grcaler reduction in calculated pulmonary vascular rcci~tance. A ‘*rcsi%ancc responder” was a patient who had il reduclion of %20% in pulmonary vascular resistance hut of ~20% in mean pulmonary artery pressure. Patients who did “01 have a reduction of 2OR in either pulmonary artcry presserc or pulmonary vascttlar resistance were considered nonresponderb. Patients who were unable to tolerate more than a
Gtgle dare uf the owl calcium blocker VW considered 4s a ,eparate proup. Statistical analysis. Mean vatucs ? SD were computed for all variahlec measured. Comoarirons between control and treated statea were made bv wired Student’s r test. Difference\ hetwecn the cfTect nf’conventional and high doses of the drug were evaluated with McNcmar’s WSI. Compariwm between the rcbponses of edch ofthe different groups were mude with one-way analysis of variance.
Results “Prew~re responders” (Pig. It. The baseline demoFraphic and hemodynamic chsracteristics and response IO calcium channel blockers of the patients arc noted in Table I, Fifteen patients were characterized as “pressure responder+..” As a proup. thcw patients had .I reducric,t in mean pulmonary awry prwure of 6.8 i 6% Ip = NS) and a I? * 25% :cducliun in pulmonary vascular resistnnce Ip C 0.05) after the first dox of a calcium channel blocker. After maximal dose challenges. the reduction in mean pulmonnry artery preswrc wtts 36.2 - 8% tp c 0.01) and in pulmonary vascular rebirldncc ws 5 0. 2 i 7% tp < 0.01). This response was associated .with a 22.7 2 1% increase in cardiac outpur Ip < 0.011 and a IO.8 z II% reduction in mean systemic presswe tp C U.ttl L No bignilicant change in heart rate. right atria1 pressure or wedge pressure wns ohserved. Resbtance responders (Fig. 21. Nineteen patients were chardcterizcd as “resistance wponders.” In this group. the reduction in mean pulmonary arlcry pressure after the initial dose of blocker was 5.7 % a% tp = NS) wherexthc reducrion in pulmonary vascular resi~ttancc wa, 21.8 5 IY% Ip < O.Illk Althuugh there was il significam reduction lranpe 5.9% lo 12%: p < tI.USI in mean syxtcmic arterial pressure with rhe maximal doire. tno further +tiiivant reduction in pulmonary artery prw,[lre 110.6 r II%) or pulmonttry vascular reriwnce t25.2 5 12%) occurred 81 the maximal
calcium
dose when during
values
were
in mew
compared
wilh
the first dose. This group alw
increase in cardiac wtp! systemic
Ihow
meawrcd
maniie*ted
a lY.i?
‘p < 0.01 I and an I I .W
reduction
pressure tp < 0.05) with
no significant
change in heart rate. nghl alrial prewre or pulmonary capillary wedge pressure. The number of do% qurcd 10 achieve maximal effecr% in the pressure and rewt.mcc responders
was 6 ? 2. I (range 3 to 111,
Nmresuonden.
Ten
palienls
were
conridered
nunrc-
who have more were hemodynamic changes arc le% likely w rc\pond 10 Ihe calcium channel blockers. Howcvcr. hecaurc we were un;rhle ro clearly dcwihc a clinical profile of a patienl who will not respond to drug challenge. we rcm;dn ohligawd 10 te\t all patients with primary pulmonary h!prrren\ion ID elucidate whether the drugs might he of ootential hemodvnamic benefit. Mechanism oire5ponses. The mea logtcal explanation for the different recpowe, to the calcium channel blockers is th;u they reprerem dift’erenr lev& of reverity of pulmonary VBIEU~K disc&e IOI. Thw. preswe rewmders would cornwise rhrne oatienl~ whose pulmonary vascular bed has the &te~r po&ial fordilalion and who therefore probably have ICII advanced di%a% The preferential influence ofthe calcium hlocken on the mdmonarv vas~ularure in lhesc paen!\ wggcxt\ heightened vawular lone in the pulmonary bed (5.10.1 Paticnl\ chardclerixd as resisumce rerponderr probably have more advanced pulmonary vawdar discart. The calcium blockers permit these patientr to adjurt to an increased cardiac output without causing a change i? pulmonary ancry preswre. However. the level of vssodilatton I\ inwfficiem to cause a Ggnificanl decrease in pulmonary awry prewre. Thw patients had comparable reductmn~ in w\ternic vaxular resistance as well. suggesting that the calcium blockers were working nonprefer&ially. Palwnts clarified as nonresponders probably have even more advanced pulmonary &ular d&se whh B fixed pulmonary varcular rcGs!ance. These patients exhihircd a reduction only in systemic vascular resiswtce. Adverse effeels. Six percent of Ihe patients tested were unable lo tokrac more than a single dose of the calcium blocker. These palicnrb probably had advanced dlseasc avocialcd with %vere right ventricular dysfunction. The onset oi hypolemion in these patients was associated with an increase in right atria1 pressure and a reduction in cardiac output. Thu\ it probably represented a negative inotropic efiect on a dysfunctional right venrricle in Ihe setting of a pulmonary vasculilr hed that has fixed pulmonary vascular rc~rlance. These ohservalions underscore the need to pay strict allention lo all hemodynamic variables. not just systemic and mdmonary artery pres~urt. when lestine vasodilators in &en!\ &h pul&~ary hypertension. _ Indication for hemcdynmnic monlloring. Our experience alw dictate\ SKI! varodilalor drugs should be administered initially IO pcllicnt> with pulmonary hypertension only with direct hemcdynamic monhoring. Whhout it. the physician cannot know how 10 adjurt Ihe dose for the patient’s maximitl hcnelicial &cl or monhor while changcel suggesting adverse hemodynamic elTec& tha might prove camrlrophic. Although we had no mortality or scrwn~~ morbidily in amv of the oauems that WC tested. adverse etl’ectr of these drug; and dealhs have been previously reported 12-141 and should not be Ignored. II iq our practice to either inhiate or mainlain digorin therapy in all ~atienis undergoing drug teuinp with the premix thal digoxin might counleracr neg_ alive inolropic effects of the calcium blockers. This hypoth-
t
IL
we hmiiedLour te\ling’ to the r/n&-d& challenges commonlv used bvolhcr invcsliealor\ 13.3.7l. we would rrol have identified the porenrial of high dew 10 caux a Ikrrge redw lion in pulmonary artcry pressure. II is presumed lhat these high dose\ arc ncedcd hecause of the high level of v:~wcorv striction wilhin rhe puhnonary arteries. It i\ also pwrihl: that the higher doles elicit other propertie\ of Ihc calcium chnnncl blockers lhal arc nol mediillcd by lhur iiclions on vol!age-dependent calcium channrls. such as modulation of the nucleoride Iran\porler. which could aRccl adenorinc uptake by crythrocyter IR). A Z!O% reduction of pulmonary vwcul~r reiiamce without substantral changes in pulmonary anery preswre was the most common response (40%). Parienl\ whh Ihl, response had an mcrease in cardiac output and a dccrcarc in pulmonary wscuIa resirlance. but not 10 Ihe magnitude of the pressure recpon\e group and not to the point where the pulmonary artery pwwre was significantly reduced. In Ihi\ croup the hirher doses of the u!cium hlockcr reruhed in iirrle. further-reduclion in pulmonary wcular resist;mcc from lhat achieved with the milial dews. Conxquenlly. we recommend that such paUerxa. if wealed with a udcium blocker on B long.term hai%. he given the lowc~t effective dose that i\ identified. Among the potential advew ~Kects of the calcium blockers are negahvc inolropic properlie< that could imparr righl ventricular performance and potenliully affect lone-term morhidhv ad rnorlalitv 19). Predicting the lypp of response. One of our more surpns. ing finding5 WBF our inabihly to predict Ihe type of re\ponre to drug testing o)n the bui, of a paliem‘r rympmms or baseline hemodynarmc status. It remains our hia\ that pa. lienfs who have had symptoms for longer perrod, of lime and
t
